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chromatin conformation

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https://www.readbyqxmd.com/read/27903283/systematic-analysis-of-chromatin-interactions-at-disease-associated-loci-links-novel-candidate-genes-to-inflammatory-bowel-disease
#1
Claartje A Meddens, Magdalena Harakalova, Noortje A M van den Dungen, Hassan Foroughi Asl, Hemme J Hijma, Edwin P J G Cuppen, Johan L M Björkegren, Folkert W Asselbergs, Edward E S Nieuwenhuis, Michal Mokry
BACKGROUND: Genome-wide association studies (GWAS) have revealed many susceptibility loci for complex genetic diseases. For most loci, the causal genes have not been identified. Currently, the identification of candidate genes is predominantly based on genes that localize close to or within identified loci. We have recently shown that 92 of the 163 inflammatory bowel disease (IBD)-loci co-localize with non-coding DNA regulatory elements (DREs). Mutations in DREs can contribute to IBD pathogenesis through dysregulation of gene expression...
November 30, 2016: Genome Biology
https://www.readbyqxmd.com/read/27895661/the-genome-conformation-as-an-integrator-of-multi-omic-data-the-example-of-damage-spreading-in-cancer
#2
Fabio Tordini, Marco Aldinucci, Luciano Milanesi, Pietro Liò, Ivan Merelli
Publicly available multi-omic databases, in particular if associated with medical annotations, are rich resources with the potential to lead a rapid transition from high-throughput molecular biology experiments to better clinical outcomes for patients. In this work, we propose a model for multi-omic data integration (i.e., genetic variations, gene expression, genome conformation, and epigenetic patterns), which exploits a multi-layer network approach to analyse, visualize, and obtain insights from such biological information, in order to use achieved results at a macroscopic level...
2016: Frontiers in Genetics
https://www.readbyqxmd.com/read/27869158/mapping-the-3d-genome-aiming-for-consilience
#3
Job Dekker
The spatial organization of genomes is studied using microscopy- and chromosome conformation capture (3C)-based methods. The two types of methods produce data that are often consistent, but there are cases where they appear discordant. These cases provide opportunities to derive better models of chromatin folding, which can reconcile the datasets.
November 21, 2016: Nature Reviews. Molecular Cell Biology
https://www.readbyqxmd.com/read/27851967/a-compendium-of-chromatin-contact-maps-reveals-spatially-active-regions-in-the-human-genome
#4
Anthony D Schmitt, Ming Hu, Inkyung Jung, Zheng Xu, Yunjiang Qiu, Catherine L Tan, Yun Li, Shin Lin, Yiing Lin, Cathy L Barr, Bing Ren
The three-dimensional configuration of DNA is integral to all nuclear processes in eukaryotes, yet our knowledge of the chromosome architecture is still limited. Genome-wide chromosome conformation capture studies have uncovered features of chromatin organization in cultured cells, but genome architecture in human tissues has yet to be explored. Here, we report the most comprehensive survey to date of chromatin organization in human tissues. Through integrative analysis of chromatin contact maps in 21 primary human tissues and cell types, we find topologically associating domains highly conserved in different tissues...
November 15, 2016: Cell Reports
https://www.readbyqxmd.com/read/27847876/overcoming-a-nucleosomal-barrier-to-replication
#5
Han-Wen Chang, Manjula Pandey, Olga I Kulaeva, Smita S Patel, Vasily M Studitsky
Efficient overcoming and accurate maintenance of chromatin structure and associated histone marks during DNA replication are essential for normal functioning of the daughter cells. However, the molecular mechanisms of replication through chromatin are unknown. We have studied traversal of uniquely positioned mononucleosomes by T7 replisome in vitro. Nucleosomes present a strong, sequence-dependent barrier for replication, with particularly strong pausing of DNA polymerase at the +(31-40) and +(41-65) regions of the nucleosomal DNA...
November 2016: Science Advances
https://www.readbyqxmd.com/read/27846223/combgap-promotes-ovarian-niche-development-and-chromatin-association-of-ecr-binding-regions-in-br-c
#6
Anna Hitrik, Malka Popliker, Dana Gancz, Zohar Mukamel, Aviezer Lifshitz, Omer Schwartzman, Amos Tanay, Lilach Gilboa
The development of niches for tissue-specific stem cells is an important aspect of stem cell biology. Determination of niche size and niche numbers during organogenesis involves precise control of gene expression. How this is achieved in the context of a complex chromatin landscape is largely unknown. Here we show that the nuclear protein Combgap (Cg) supports correct ovarian niche formation in Drosophila by controlling ecdysone-Receptor (EcR)- mediated transcription and long-range chromatin contacts in the broad locus (BR-C)...
November 2016: PLoS Genetics
https://www.readbyqxmd.com/read/27832542/unbiased-interrogation-of-3d-genome-topology-using-chromosome-conformation-capture-coupled-to-high-throughput-sequencing-4c-seq
#7
Rutger W W Brouwer, Mirjam C G N van den Hout, Wilfred F J van IJcken, Eric Soler, Ralph Stadhouders
The development and widespread implementation of chromosome conformation capture (3C) technology has allowed unprecedented new insight into how chromosomes are folded in three-dimensional (3D) space. 3C and its derivatives have contributed tremendously to the now widely accepted view that genome topology plays an important role in many major cellular processes, at a chromosome-wide scale, but certainly also at the level of individual genetic loci. A particularly popular application of 3C technology is to study transcriptional regulation, allowing researchers to draw maps of gene regulatory connections beyond the linear genome through addition of the third dimension...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27801941/non-coding-variation-in-disorders-of-sex-development
#8
REVIEW
Dorien Baetens, Bérénice B Mendonça, Hannah Verdin, Martine Cools, Elfride De Baere
Genetic studies in Disorders of Sex Development (DSD), representing a wide spectrum of developmental or functional conditions of the gonad, have mainly been oriented towards the coding genome. Application of genomic technologies, such as whole exome sequencing, result in a molecular genetic diagnosis in ~50% of cases with DSD. Many of the genes mutated in DSD encode transcription factors such as SRY, SOX9, NR5A1, and FOXL2, characterized by a strictly regulated spatiotemporal expression. Hence, it can be hypothesized that at least part of the missing genetic variation in DSD can be explained by non-coding mutations in regulatory elements that alter gene expression, either by reduced, mis- or overexpression of their target genes...
November 1, 2016: Clinical Genetics
https://www.readbyqxmd.com/read/27799067/identification-of-a-rai1-associated-disease-network-through-integration-of-exome-sequencing-transcriptomics-and-3d-genomics
#9
Maria Nicla Loviglio, Christine R Beck, Janson J White, Marion Leleu, Tamar Harel, Nicolas Guex, Anne Niknejad, Weimin Bi, Edward S Chen, Isaac Crespo, Jiong Yan, Wu-Lin Charng, Shen Gu, Ping Fang, Zeynep Coban-Akdemir, Chad A Shaw, Shalini N Jhangiani, Donna M Muzny, Richard A Gibbs, Jacques Rougemont, Ioannis Xenarios, James R Lupski, Alexandre Reymond
BACKGROUND: Smith-Magenis syndrome (SMS) is a developmental disability/multiple congenital anomaly disorder resulting from haploinsufficiency of RAI1. It is characterized by distinctive facial features, brachydactyly, sleep disturbances, and stereotypic behaviors. METHODS: We investigated a cohort of 15 individuals with a clinical suspicion of SMS who showed neither deletion in the SMS critical region nor damaging variants in RAI1 using whole exome sequencing. A combination of network analysis (co-expression and biomedical text mining), transcriptomics, and circularized chromatin conformation capture (4C-seq) was applied to verify whether modified genes are part of the same disease network as known SMS-causing genes...
November 1, 2016: Genome Medicine
https://www.readbyqxmd.com/read/27798106/dna-methylation-independent-removable-insulator-controls-chromatin-remodeling-at-the-hoxa-locus-via-retinoic-acid-signaling
#10
Ko Ishihara, Masafumi Nakamoto, Mitsuyoshi Nakao
Chromatin insulators partition the genome into functional units to control gene expression, particularly in complex chromosomal regions. The CCCTC-binding factor (CTCF) is an insulator-binding protein that functions in transcriptional regulation and higher-order chromatin formation. Variable CTCF-binding sites have been identified to be cell type-specific partly due to differential DNA methylation. Here, we show that DNA methylation-independent removable CTCF insulator is responsible for retinoic acid (RA)-mediated higher-order chromatin remodeling in the human HOXA gene locus...
October 24, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/27795369/combined-systems-approaches-reveal-a-multistage-mode-of-action-of-a-marine-antimicrobial-peptide-against-pathogenic-escherichia-coli-and-its-protective-effect-against-bacterial-peritonitis-and-endotoxemia
#11
Xiumin Wang, Da Teng, Ruoyu Mao, Na Yang, Ya Hao, Jianhua Wang
A marine arenicin-3 derivative N4 displayed potent antibacterial activity against Gram-negative bacteria, but its antibacterial mode of action remains elusive. The mechanism of action of N4 against pathogenic Escherichia coli was first researched by combined cytological and transcriptomic techniques in this study. The N4 peptide permeabilized the outer membrane within 1 min, disrupted the plasma membrane after 0.5 h, and localized the cytoplasm within 5 min. Gel retardation and CD spectra analyses demonstrated that N4 bound specifically to DNA and disrupted the DNA conformation from the B- to C-type...
October 24, 2016: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/27791029/crystal-structure-of-the-dna-binding-domain-of-the-transcription-factor-t-bet-suggests-simultaneous-recognition-of-distant-genome-sites
#12
Ce Feng Liu, Gabriel S Brandt, Quyen Q Hoang, Natalia Naumova, Vanja Lazarevic, Eun Sook Hwang, Job Dekker, Laurie H Glimcher, Dagmar Ringe, Gregory A Petsko
The transcription factor T-bet (Tbox protein expressed in T cells) is one of the master regulators of both the innate and adaptive immune responses. It plays a central role in T-cell lineage commitment, where it controls the TH1 response, and in gene regulation in plasma B-cells and dendritic cells. T-bet is a member of the Tbox family of transcription factors; however, T-bet coordinately regulates the expression of many more genes than other Tbox proteins. A central unresolved question is how T-bet is able to simultaneously recognize distant Tbox binding sites, which may be located thousands of base pairs away...
October 25, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27789700/reciprocal-regulation-of-chromatin-state-and-architecture-by-hotairm1-contributes-to-temporal-collinear-hoxa-gene-activation
#13
Xue Q D Wang, Josée Dostie
Thousands of long non-coding RNAs (lncRNAs) have been identified in mammals, many of which represent important regulators of gene expression. However, the mechanisms used by lncRNAs to control transcription remain largely uncharacterized. Here, we report on HOTAIRM1, a promising lncRNA biomarker in leukemia and solid tumors. We find that HOTAIRM1 contributes to three-dimensional chromatin organization changes required for the temporal collinear activation of HOXA genes. We show that distinct HOTAIRM1 variants preferentially associate with either UTX/MLL or PRC2 complexes to modulate the levels of activating and silencing marks at the bivalent domain...
October 26, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27789693/3dsnp-a-database-for-linking-human-noncoding-snps-to-their-three-dimensional-interacting-genes
#14
Yiming Lu, Cheng Quan, Hebing Chen, Xiaochen Bo, Chenggang Zhang
The vast noncoding portion of the human genome harbors a rich array of functional elements and disease-causing regulatory variants. Recent high-throughput chromosome conformation capture studies have outlined the principles of these elements interacting and regulating the expression of distal target genes through three-dimensional (3D) chromatin looping. Here we present 3DSNP, an integrated database for annotating human noncoding variants by exploring their roles in the distal interactions between genes and regulatory elements...
October 26, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27782467/a-fast-open-source-implementation-of-adaptive-biasing-potentials-uncovers-a-ligand-design-strategy-for-the-chromatin-regulator-brd4
#15
Bradley M Dickson, Parker W de Waal, Zachary H Ramjan, H Eric Xu, Scott B Rothbart
In this communication we introduce an efficient implementation of adaptive biasing that greatly improves the speed of free energy computation in molecular dynamics simulations. We investigated the use of accelerated simulations to inform on compound design using a recently reported and clinically relevant inhibitor of the chromatin regulator BRD4 (bromodomain-containing protein 4). Benchmarking on our local compute cluster, our implementation achieves up to 2.5 times more force calls per day than plumed2. Results of five 1 μs-long simulations are presented, which reveal a conformational switch in the BRD4 inhibitor between a binding competent and incompetent state...
October 21, 2016: Journal of Chemical Physics
https://www.readbyqxmd.com/read/27774982/genetic-variation-at-the-8q24-21-renal-cancer-susceptibility-locus-affects-hif-binding-to-a-myc-enhancer
#16
Steffen Grampp, James L Platt, Victoria Lauer, Rafik Salama, Franziska Kranz, Viviana K Neumann, Sven Wach, Christine Stöhr, Arndt Hartmann, Kai-Uwe Eckardt, Peter J Ratcliffe, David R Mole, Johannes Schödel
Clear cell renal cell carcinoma (ccRCC) is characterized by loss of function of the von Hippel-Lindau tumour suppressor (VHL) and unrestrained activation of hypoxia-inducible transcription factors (HIFs). Genetic and epigenetic determinants have an impact on HIF pathways. A recent genome-wide association study on renal cancer susceptibility identified single-nucleotide polymorphisms (SNPs) in an intergenic region located between the oncogenes MYC and PVT1. Here using assays of chromatin conformation, allele-specific chromatin immunoprecipitation and genome editing, we show that HIF binding to this regulatory element is necessary to trans-activate MYC and PVT1 expression specifically in cells of renal tubular origins...
October 24, 2016: Nature Communications
https://www.readbyqxmd.com/read/27771863/solution-nmr-structure-of-the-hltf-hiran-domain-a-conserved-module-in-swi2-snf2-dna-damage-tolerance-proteins
#17
Dmitry M Korzhnev, Dante Neculai, Sirano Dhe-Paganon, Cheryl H Arrowsmith, Irina Bezsonova
HLTF is a SWI2/SNF2-family ATP-dependent chromatin remodeling enzyme that acts in the error-free branch of DNA damage tolerance (DDT), a cellular mechanism that enables replication of damaged DNA while leaving damage repair for a later time. Human HLTF and a closely related protein SHPRH, as well as their yeast homologue Rad5, are multi-functional enzymes that share E3 ubiquitin-ligase activity required for activation of the error-free DDT. HLTF and Rad5 also function as ATP-dependent dsDNA translocases and possess replication fork reversal activities...
October 22, 2016: Journal of Biomolecular NMR
https://www.readbyqxmd.com/read/27770354/chromatin-conformation-capture-based-analysis-of-nuclear-architecture
#18
Stefan Grob, Ueli Grossniklaus
Nuclear organization and higher-order chromosome structure in interphase nuclei are thought to have important effects on fundamental biological processes, including chromosome condensation, replication, and transcription. Until recently, however, nuclear organization could only be analyzed microscopically. The development of chromatin conformation capture (3C)-based techniques now allows a detailed look at chromosomal architecture from the level of individual loci to the entire genome. Here we provide a robust Hi-C protocol, allowing the analysis of nuclear organization in nuclei from different wild-type and mutant plant tissues...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27766670/spatial-organization-of-the-schizosaccharomyces-pombe-genome-within-the-nucleus
#19
Atsushi Matsuda, Haruhiko Asakawa, Tokuko Haraguchi, Yasushi Hiraoka
The fission yeast Schizosaccharomyces pombe is a useful experimental system for studying the organization of chromosomes within the cell nucleus. S. pombe has a small genome that is organized into three chromosomes. The small size of the genome and the small number of chromosomes are advantageous for cytological and genome-wide studies of chromosomes; however, the small size of the nucleus impedes microscopic observations owing to limits in spatial resolution during imaging. Recent advances in microscopy, such as super-resolution microscopy, have greatly expanded the use of S...
October 21, 2016: Yeast
https://www.readbyqxmd.com/read/27764097/dynamic-nucleosome-movement-provides-structural-information-of-topological-chromatin-domains-in-living-human-cells
#20
Soya Shinkai, Tadasu Nozaki, Kazuhiro Maeshima, Yuichi Togashi
The mammalian genome is organized into submegabase-sized chromatin domains (CDs) including topologically associating domains, which have been identified using chromosome conformation capture-based methods. Single-nucleosome imaging in living mammalian cells has revealed subdiffusively dynamic nucleosome movement. It is unclear how single nucleosomes within CDs fluctuate and how the CD structure reflects the nucleosome movement. Here, we present a polymer model wherein CDs are characterized by fractal dimensions and the nucleosome fibers fluctuate in a viscoelastic medium with memory...
October 2016: PLoS Computational Biology
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